9-Thiaprostaglandin compositions

ABSTRACT

7-(3 Alpha -(3-hydroxy-3-hydrocarbylpropyl or -1-propenyl)-4hydroxy-tetrahydro-2 Beta -thienyl)-heptanoic or 5-heptenoic acids, sulfoxides, sulfones, esters or salts thereof are stable, prostaglandin-like acting agents.

United States Patent Vlattas Apr. 29, 1975 9-THIAPROSTAGLANDINCOMPOSITIONS Primarr Examiner-Sam Rosen 75 I t: Id Vltt,S .N..

[ i or mos a as ummlt J Attorney, Agent, or Firm--Joseph G. Kolodny;

[73] Asslgneez Ciba-Geigy Corporation, Ardsley, Th dore O, Groeger; JohnJ Maimer [22] Filed: May 18, 1973 2| Appl. No.2 361,752 [57] ABSTRACT7-[ 3a-( 3-hydroxy-3 hydrocarbylpropyl or l [52] [1.8. CI. 424/275;260/3321; 260/3322 A P p y!)- -hydro y-tetrahydro-ZB-thienyIJ-heptanoic[51] Int. Cl .3 A6lk 27/00 r 5-h pt noic a i lfoxid lf n esters or [58]Field of Search 424/275; 260/332.2 A, 332,1 salts thereof are stable,prostaglandin-Iike acting agents.

[56] References Cited UNITED STATES PATENTS 3 Claims. N0 Drawings3.69I.202 9/l972 O'Munt 424/275 9-THIAPROSTAGLANDIN COMPOSITIONS SUMMARYOF THE INVENTION The present invention concerns and has for its objectthe provision of new 7-[ 3a-( 3-hydroxy-3- hydrocarbylpropyl or-l-propenor ynyl)-4-hydroxytetrahydro-ZB-thienyll-heptanoic orS-heptenoic acids, more particularly of those corresponding to Formula l1 1 3 no ...CH=C con l l l\ l R1 R9 R3 (1) s CHPA (ca -cooa wherein R ishydrogen, one metal equivalent or an aliphatic, cycloaliphatic,araliphatic or aromatic radical, A is ethylene or ethenylene, each of R,and R is hydrogen or lower alkyl, R is an aliphatic, cycloaliphatic oraraliphatic radical and x is an integer from to 2, or the l,2-dihydro or-dehydro derivatives thereof, corresponding pharmaceutical compositionsand methods for the preparation and application of these products, whichare useful prostaglandin-like acting smooth muscle contractants andantiasthmatic agents, but more stable than the easily dehydratingprostaglandins of the E series.

DESCRIPTION OF THE PREFERRED EMBODIMENTS An aliphatic radical R or Rrepresents preferably lower alkyl, as is the case with R. and R e.g.methyl, ethyl, nor i-propyl, -butyl, -pentyl, -hexyl or -heptyl; loweralkenyl, e.g. allyl or methallyl', or lower alkynyl, e.g. ethynyl orpropargyl. The term lower" referred to above and hereinafter inconnection with organic radicals or compounds respectively, defines suchwith up to 7, preferably up to 4, carbon atoms. R;, also representshigher alkyl, especially such with 8 to 12 carbon atoms, such as nori-octyl, -nonyl, -decyl, -undecyl or -dodecyl.

Said lower cycloaliphatic radicals R and R are preferably 3 to 7ring-membered cycloalkyl, cycloalkenyl or (cycloalkyl orcycloalkenyl)-lower alkyl groups, e.g. cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl; cyclopent-l-enyl or cyclohex-l or 3-enyl;cyclopropylmethyl, cyclobutylmethyl, lor 2-cyclopentylethyl;cyclopent-3-enylmethyl or cyclohex-l-enylmethyl.

Said araliphatic or aromatic radicals R or R are preferably isocyclic,monocyclic radicals, such as phenyllower alkyl or phenyl groups,unsubstituted or substituted in the aromatic ring by one or more thanone, especially one or two, of the same or different substituents, suchas lower alkyl, e.g. methyl, ethyl, nor ipropyl or -butyl; lower alkoxy,e.g. methoxy, ethoxy, N- or i-propoxy or -butoxy; lower alkylenedioxy,e.g. methylenedioxy, l,lor 1,2-ethylenedioxy; halogeno, e.g. fluoro,chloro, bromo or iodo; trifluoromethyl; nitro or amino, such as di-loweralkylamino, e.g. dimethylamino or diethylamino. Said aliphatic radicals,especially lower alkyl groups R can also be substituted by one of saidlower alkoxy groups or one, or up to the maximum number of halogenatoms, as is the case in trifluoromethyl, Z-(methoxy, ethoxy, chloro,bromo or iodo)-ethyl, -propyl or -butyl, 2,2-dichloro-ethyl, -propyl or-butyl, 2,2,2-trichloroethyl, 3-(methoxy, ethoxy, chloro orbromo)-propyl or -butyl, 4-(methoxy or chloro)-butyl.

The compounds of the invention exhibit valuable, prostaglandin-likeproperties, especially smooth muscle contracting and antiasthmaticactivity. This can be demonstrated either in vitro or in vivo tests,using advantageously mammals, such as mice, rats, guinea pigs or dogs astest objects, or isolated organs thereof. The in vitro tests areperformed with the guinea pig ileum in a standard organ bath, e.g.physiological saline. The compounds of the invention, when added to saidbath in such amounts to reach concentrations down to about 10 molar,contract the isolated ileum, Histamine hydrochloride and prostaglandin Eare used as a positive standard and the usual experiments include thecontrol for vehicle and buffer effects.

Antiasthmatic activity is estimated in dogs, who are naturally sensitiveto ascaris antigens, causing asthma like syndroms after inhalation ofsaid nebulized antigens. The compounds of the invention are administeredintravenously 30-60 minutes after antigen-challenge and efficacy isestimated by the change in respiratoryrate and airway-resistance.

Moreover, anti-fertility effects are tested in rats or hamsters, e.g. byadministering the compounds of the invention to pregnant hamsters, forexample 2.5 to ID mg/kg thereof, subcutaneously once on day five ofpregnancy, and inspecting on the eleventh day the uterus thereof forimplantation sites and surviving embryos. Also smaller doses can be usedfor intravenous or intrauterine administration, or larger amounts fororal administration, e.g. to spontaneous hypertensive rats, whose bloodpressure is monitored by standard means, and is reduced by saidcompounds.

Accordingly, the compounds of the invention can be applied enterally orparenterally, e.g. by inhalation of a nebulized aqueous solution, or byperoral, subcutaneous, intramuscular, intraveneous or intrauterineadministration, in the dosage range known for the naturalprostaglandins. According to the test results obtained, they are usefulantiasthmatic, hypotensive, abortifacient and luteolytic agents, forexample, in the treatment or management of hypertension, especiallyfertility. They are also valuable intermediates of other preparations,preferably of pharmacologically useful products.

Preferred compounds of the invention are those of Formula I, in whicheach of R and R is lower alkyl, lower alkenyl, lower alkynyl, (3 to 7ring-membered cycloalkyl or cycloalkenyD-C H wherein m is an integerfrom 0 to 4, or Ph-C l-l wherein Ph is phenyl, (lower alkyl)-phenyl,(lower alkoxy)-phenyl, (lower alkylenedioxy)-phenyl, (halogeno)-phenyl,(trifluoromethyH-phenyl, (nitro)-phenyl or (di-lower alkylamino)-phenyland n is an integer from 1 to 4, R is also hydrogen, Ph, an alkali metalor one equivalent of an alkaline earth metal and R is also (lower alkoxyor halo)-lower alkyl, A is ethylene or ethenylene, R, and R are hydrogenor lower alkyl, or the l,2-dihydroderivatives thereof, and x is 0 to 2.

More active and stable are those 301,401- and 38,43- dihydroxycompoundsof Formula I, wherein R is hydrogen, sodium, potassium, lower alkyl orPh-C,,H wherein n is an integer from 1 to 4 and Ph' is phenyl, tolyl,anisyl, fluorophenyl or chlorophenyl, A is ethylene or cis-ethenylene,each of R, and R are hydrogen or lower alkyl, and R is lower alkyl,lower alkoxyalkyl perfluoro-lower alkyl, (3 to 6 ring-memberedcycloalkyl)-C,,,l-l or Ph'-C,,H,,,, wherein m is an integer from to 4,and x is such from 0 to 2.

The highest degree of activity and stability is exhibited by compoundsof Formula ll wherein R, is hydrogen, sodium, potassium or alkyl with upto 4 carbon atoms, A is ethylene or cisethenylene, R is hydrogen ormethyl and R is npentyl, n-hexyl, n-heptyl, 2-,3- or 4-(cyclopropyl,cyclopentyl or phenyl)-ethyl, -propyl or -butyl and x is 0-2.

Of said compounds of Formula ll, it is advantageous to select thosewherein R, is hydrogen, sodium or potassium, A is ethylene orcis-ethenylene, R is hydrogen or methyl, x is 0 to 2 and R is n-pentyl,n-hexyl or 3- phenylpropyl, due to their outstanding activity andstability.

The compounds of the invention are prepared according to methods knownper se, for example by:

a. reducing in a corresponding 7-[3a-(3-oxo-3- hydrocarbylpropyl orl-propenor ynyl)-4 -hydroxy-tetrahydro-ZB-thienyll-heptanor S-enoicacid, or a functional acidor hydroxy-derivative, the sulfoxide orsulfone thereof, the 0x0 group to hydroxy b. oxidizing a corresponding7-[3a-(3-hydroxy-3- hydrocarbylpropyl or l-propenor ynyl)-4-hydroxy-tetrahydro-2B-thienyll-heptanal or 5- heptenal, or a functionalhydroxy-derivative, the sulfoxide or sulfone thereof, to thecorresponding acid, or

c. reacting the 2B-(6-carboxyhexyl or 2-enyl)-4-hydroxy-tetrahydrothiophene-3a-carboxaldehyde, or a functional acidorhydroxyderivative, the sulfoxide or sulfone thereof, with the ylid ofFormula lll wherein X is lower alkyl or phenyl and Y is metallized oretherified hydroxy or d. reacting a corresponding [3a-(3-hydroxy-3-hydrocarbylpropyl or -l-propenor ynyl)-4-hydroxy-tetrahydro-ZB-thienyl]-acetaldehyde, or a functional hydroxyderivative, the sulfoxide or sulfone thereof, with the compound ofFormula IV wherein X has the above meaning and Z is functionallyconverted carboxy, and hydrolyzing any resulting hydroxy derivative inbasic or acidic media or any resulting acid amide or nitrile in strongbasic media and, if desired, oxidizing resulting compounds with x 0 tosuch with x l or 2, or esterifying or salifying any resulting acid orhydrolyzing esters or salts or hydrogenating any resulting dehydroderivative until the desired amount of hydrogen is consumed.

A metallized compound III is preferably derived from an alkali metal,e.g. sodium or potassium, and in a corresponding ether Y is preferablytetrahydropyranyloxy or methoxymethoxy. A functional acid derivativeused in the above reactions is preferably a metal salt or an ester, e.g.such mentioned above for the compounds of Formula I, or advantageouslythe nitrile. A functional hydroxy derivative is either an ester orether, such as a lower alkanoic acid ester, e.g. the acetate orpropionate, but advantageously the Z-tetrahydropyranyl ether.

The reduction according to item a) is advantageously carried out eitherwith simple or complex light metal hydrides, such as borohydrides oralkali metal or zinc boronor aluminum-hydrides or lower alkoxyhydrides,e.g. lithium aluminumhydride, sodium or zinc borohydride', lithiumtri-t-butoxyaluminumhydride or triethoxyaluminumhydride, or according toMeerwein- Ponndorf-Verley with aluminum lower alkoxides, e.g. theethoxide or advantageously the isopropoxide, preferably in the presenceof a lower alkanol, e.g. isopropanol and/or a dihaloaluminum loweralkoxide, e.g. dichloroaluminum isopropoxide.

The oxidation according to item b) is carried out in the conventionalmanner for oxidizing aldehydes, for example with catalytically activatedor nascent oxygen respectively, the latter is derived from conventionaloxidation agents, such as oxidizing acids or suitable salts oranhydrides thereof, e.g. periodic acid, sodium hypochlorite, chromic,ferric or cupric halides or sulfates, manganese lV, chromium Vl,vanadium V, mercuric or silver oxide, in acidic or alkaline media. Saidagents are used in the equivalent amounts and/or under carefulcondition, in order to prevent oxidations at other sites of themolecule.

The reactions according to items 0) and d) are carried out according tothe Wittig Reaction, i.e. either with the isolated reactants of FormulaeIII or IV, or the precursors thereof, e.g. by combining thecorresponding phosphonium halide with a strong base, such as an alkalimetal hydroxide, alkoxide, alkyl or phenyl compound flrst, whereupon thealdehyde is added. Reaction c) is followed by acid hydrolysis in orderto eliminate Y.

Any resulting hydroxy or carboxy derivative is hydrolyzed in the usualmanner, for example a lower alkanoic acid ester of the 3 -hydroxycompound, or the amide or nitrile or a lower alkyl ester of theheptanoic acid, with a base, such as an aqueous alkali metal hydroxideor carbonate. or an ether of the 3 -hydroxy compound with an acid, suchas a mineral, e.g. hydrohalic or sulfuric acid. Any resultingtetrahydrothiophene may be oxidized to the sulfoxide with conventional,mild oxidizing agents such as alkali metal periodates, e.g. sodiumperiodate. The corresponding sulfones are obtained with strongeroxidation agents, such as hydrogen peroxide or aliphatic or aromaticperacids, e.g. peracetic or mchloroperbenzoic acid. Any resulting acidmay be esterified or salified in the usual manner, for example, withlower alkanols in the presence of mineral acids, preferably with lowerdiazoalkanes, or corresponding bases or ion exchangers respectively. Anyresulting dehydro derivative (e.g. A=ethenylene) can be selectivelyhydrogenated with rhodium catalysts or diirnine. Said hydrogenation ispreferably carried out prior to said hydrolysis of the 3 -hydroxyderivatives, in order to protect the prop-l-enyl double bond.

The starting material used can be prepared according to the followingformula scheme, illustrated by the examples herein:

Accordingly, in case R is A-(CH -CN, compounds of Formula X are startingmaterials for the reduction mentioned under item a), compounds ofFormula [X are starting materials for c) and those of Formula XI suchfor d). In case R in Formula X contains said group capable of beingconverted into CH0, and such compound is reduced as in a), whereupon CHOis liber- HC- COOR (Iva) I-IC- (CH -R .COOR e) Na V-S-CHg-COOR i (v) s(Cha -R r) v NaBI-lq h+ HO j .0003

1 n ?)p ThpO M .0001? a) v1+ l J (VII) ThpO .cu oa 11) VII LiAlm, i(VIII) 5 (cu -m ThpO ".0140 1) VIII H2 l /1 (IX) 5) IX (X) I=C c=0 ThpO.CH=C-C=O 3 l l w) T l l R1 R. J {l 3 J s CH -R a l. lX 111 i a "I", no.cn=c c on wherein R is either A-(CHzlrCN or a group capable of beingconverted into CHO, such as an etherified dihydroxymethyl (acetal)group, derived, for example, from lower alkanols or glycols, e.g.methanol, ethanol or ethylene glycol, V is hydrogen, an alkali metal oran ammonium radical derived from a tertiary base, e.g. a trialkylarnineor pyridine, and p is the integer O or I.

ll 1) 0014- ori -R (X)3P=CH-CHO Hmon -R m) XII v-s- CHE-R5 i I in) XIII(x) P=C c=o cn -s-cnsa -R1, 1 3 l 1 s \CHQ-CHO l or; -S-CH-CH2-R i atedin acidic media, starting material for b) is obtained. Said products canbe converted into the other starting materials as described above forthe resulting compounds of Formula I.

Another method for the preparation of the starting materials mentionedunder item a) to d) is the following:

HC-CHO (XII) R ca -CHO 2 (XIII) R CH -CH C (i=0 1 R1 R3 (XIVl "(l-- CCHHYUH ClL-C--U-- 1. I i xilv an: :H mu a, I I (h 2)2 l0 H S-LIH--CH-R;; H1 3 J 1.2V EH, U l llU T -c. .Cll -S) 3 Q CH H1 (XJl 1 H "I}iO..... a.. 1l u 1.I.[t H I J (XVII) s cn -A- (wa -c0012 wherein s i5Said g p p le of being flfl fled compound is analogously reduced as ina), whereupon into CH0 and other Symbols have meanings 5 CH0 isliberated in acidic media, starting material for given above.Accordingly, compounds of Formula XVI d) is bt i d,

are starting materials for a) and XVII for c) if R, is A- (CH -CN. lncase R in Formulae X and XVI is said Another process for said startingmaterial is depicted group capable of being converted into CH0 and suchby the following scheme:

I (XVIII) t) XIX (0 11 cits-c 11 HO ..cu ocww) XXI] 'I'ior mun-saltsThpO ..il...CIi-M'l'hp 1 3 (XXHI) s \CHFCHO x) XXIII (X3)P=CH-(CHE)3-ZThpC ....CH OThp (XXIV) s CH2- CH=CH- (cu;- 2?

. C11,. OH

CH=CH- can -7; za) xxv1+ 1. i D 3 wherein W is H, or O. The latter VIIIis converted to the corresponding X as shown above.

Finally, selected compounds of the invention, or starting materials, canbe prepared as follows:

2d) 1min By c042 xxr: 1

e mi or H The above steps (d), (j), (k), (l), (n), (s), (t). (u), (x)and (y) are carried out analogous to (c) or (d); the condensationsaccording to (e) or (m) advantageously in di-lower alkylsulfoxides, e.g.dimethylsulfoxide, followed by acid treatment; the reductions accordingto (f) and (h) are performed analogously to (a); the etherifications,ketalizations or transketalizations according to (g), (o), (v) or (1)respectively are advantageously carried out in the presence of anorganic acid, e.g. picric or p-toluenesulfonic acid and an inertdiluent, such as a halogenalkane, e.g. methylene chloride; the oxidationaccording to (i) is performed according to (b), preferably with the useof heavy metal oxides, e.g. silver or chromium Vl oxide, advantageouslyin inert solvents, such as halogenalkanes and/or pyridine. Thering-closure according to (p) occurs spontaneously after acid hydrolysisof the bis-ketal whereas that according to (q) requires first acidhydrolysis to convert R to formyl and the following aldol condensationoccurs under basic conditions, e.g. in the presence of alkali metals,their alkoxides or amides. The esterification or benzylation accordingto (r) and (z) are carried out in the usual manner, preferably in thepresence of a base, e.g. pyridine, or sodium hydride respectively. Saidintermediates, e.g. Vlll, can also be oxidized to the sulfoxides orsulfones, as shown above for compounds I.

Resulting mixtures of isomers can be separated into the single isomersby methods in themselves known, e.g. by fractional distillation,crystallization and/or chromatography. Racemic products can likewise beresolved into the optical antipodes, for example, by sepa ration ofdiastereomeric esters or salts thereof, e.g. by the fractionalcrystallization of dor l-2-pyrrolidone-3- carboxylates, -3B-acetoxy-A-etienates, -a-(2,4,5,7-tetranitro-9-fluorenylideneaminooxy)'propionates or salts of dorl-a-phenethylamine, -lphenyl-2- propylamine or -dihydroabietylamine.

The above reactions are carried out according to standard methods, inthe presence or absence of diluents, preferably such as are inert to thereagents and are solvents thereof, of catalysts, condensing,neutralizing agents and/or inert atmospheres, at low temperatures, roomtemperature or elevated temperatures, at atmospheric or superatmosphericpressure. For example, any generated mineral or sulfonic acid may beneu- ThpO tralized with inorganic or organic bases, such as alkali oralkaline earth metal hydroxides, carbonates or bicarbonates or nitrogenbases, such as tri-lower alkylamines or pyridine.

C C- Lil L i (XXVlII s War u C C-C OH (CH2) -Rl;

(XXIX) The invention also comprises any modification of the aboveprocess, wherein a compound resulting as an intermediate at any stagethereof, is used as starting material and the remaining steps arecarried out or the process is discontinued at any stage thereof, or inwhich the starting material is formed under the reaction conditions oris used in the form of its salts or other derivatives. in the aboveprocesses, those starting materials are advantageously selected, whichyield the abovedescribed preferred embodiments of the invention.

The pharmacologically active compounds of the invention are useful inthe manufacture of pharmaceutical compositions containing an effectiveamount thereof in conjunction or admixture with excipients suitable foreither enteral or parenteral application. Preferred are tablets andgelatin capsules comprising the active ingredient together with (a)diluents, e.g. lactose, dextrose, sucrose. mannitol, sorbitol, celluloseand/or glycine, b) lubricants, e.g. silica, talcum, stearic acid, itsmagnesium or calcium salt and/or polyethyleneglycol, for tablets also(c) binders, e.g. magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose and/orpolyvinylpyrrolidone, if desired, (d) disintegrants, e.g. starches,agar, alginic acid or its sodium salt, enzymes of the binders oreffervescent mixtures and/or (e) adsorbents, colorants, flavors,sweeteners and coating agents, e.g. concentrated aqueous sugar solutionscontaining gum arabic, talcum and/or titanium dioxide, or solutions oflacquers in easily volatile organic solvents, in order to obtain regularor sustained release formulations. lnjectable compositions arepreferably aqueous isotonic solutions or suspensions, and suppositoriesare advantageously fatty emulsions or suspensions, e.g. in cocoa butter.They may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts forregulating the osmotic pressure and/or buffers. They may also containother therapeutic agents, e.g. diuretics and/or psychotherapeutics as inU.S. Pat. Nos. 3,08l,230 or 3,499,082. Said compositions are preparedaccording to conventional mixing, granulating or coating methodsrespectively and contain about 0.00l to percent, preferably about I to50 percent of the active ingredient.

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees Centigrade, and all parts wherever given are parts by weight.If not otherwise stated, all evaporations are carried out under reducedpressure, the infrared spectra are obtained from about 15 percentsolutions in chloroform and the N.M.R. spectra from about 10 percentsolutions in deuterochloroform at 60 Mc/sec. with tetramethylsilane aszero.

EXAMPLE 1 To the solution of 53 mg of7-[3a-(3-oxo-l-transoctenyl)-4B-hydroxy-tetrahydro-ZB-thienyl]-heptanoicacid nitrile in 1 ml ofdiethyl ether, 3 ml of ethereal zinc borohydride{prepared according to Gensler et al, J. Am. Chem. Soc. 82, 6074 (1960)]are added at once and the mixture is stirred at room temperature for twohours. Thereupon 0.1 ml of water are added, followed by 0.1 ml ofglacial acetic acid and the mixture is stirred for five minutes. It isdiluted with 50 ml of diethyl ether, washed with saturated aqueoussodium chloride, dried and evaporated. The residue is subjected topreparative thin-layer chromatography on silica gel plates (l mm thick),eluted with ethyl acetatemethylene chloride l :l and of the two mainfractions the slower moving isomer with Rf 0.26 isolated, to yield the7-[ 3cx-( 3B-hydroxyl -trans-octenyl )-4B-hydroxy-tetrahydro-ZB-thienyl]-heptanoic acid nitrile of the formula rgn- (CH M- CH n on S 2)6 LN melting at 67-69 after recrystallizationfrom diethyl ether-n-hexane.

The mixture of 69 mg thereof, 2 ml of methanol, 1 ml of water and 0.2 mlof 20 percent aqueous potassium hydroxide is heated in a sealed tube toll5-l20 for 72 hours and evaporated. The residue is taken up in ml ofwater and 10 ml of saturated aqueous sodium chloride. the mixtureneutralized with dry ice and extracted with diethyl ether. The extractis dried, evaporated and the residue recrystallized from diethyl ether,to yield the 7-[3a-(3B-hydroxy-l-trans-octenyl)-4B-hydroxy-tetrahydro-ZB-thienyl]-heptanoic acid of the formula HO 1 =r UH-(011 ch.

L n OH s (ca coon melting at 8890.

The starting material is prepared as follows: The mixture of 1.8 g of9-cyano-2-nonenal, 1.4 g of 2,2-diethoxy-ethanethiol and 50 pl oftriethylamine is allowed to stand at room temperature for 48 hours. Itis taken up in 100 ml of diethyl ether, the solution washed with water,dried and evaporated, to yield the 9-cyano-3- a (CH2) c on on on on(CH2)6 on 14 (c a m ca-ca -s having an Rf= 0.33.

The mixture of 1.2 g thereof, 0.34 g of ethylene glycol, 30 mg ofp-toluenesulfonic acid and 25 ml of benzene is refluxed for 15 hours ona water separator. After cooling it is diluted with ml of diethyl ether,the solution washed with 10 percent aqueous potassium bicarbonate andwater, dried and evaporated, to yield the bis-ethylene ketal of thel-cyano-IO- formylmethylmercapto-8-hexadecen-6-one showing in the NMRspectrum peaks at 5.4, 5.02, 3.93, 2.66 and 2.34 ppm.

The mixture of l.l5 g thereof, 30 ml of acetone and 0.19 g ofp-toluenesulfonic acid is stirred for 40 hours at room temperature undernitrogen. It is evaporated at room temperature, the residue taken up indiethyl ether, the solution washed with l0% aqueous potassium carbonateand water, dried and evaporated. The residue is subjected to preparativethin-layer chroma tography on silica gel, eluted three times with ethylacetate-methylene chloride (9:1) and the two main fractions having Rf0.70 and 0.55 are isolated. The slower moving isomer (Rf= 0.55) is thedesired 7-130:- (3-oxol -trans-octenyl )-43-hydroxy-tetrahydro-ZB-thienyll-heptanoic acid nitrile, showing in the mass spectrum fragmentsof 337, 319, 262, 220 and 209 mle.

The faster moving isomer is the corresponding 28, 3a, 4a-compound. Itcan be reduced and hydrolized as shown above, to yield the7-[3a-(3a-hydroxy-l-transoctenyl )-4a-hydroxy-tetrahydro-2B-thienyll-heptanoic acid of the formula S/ (CH -cooa melting at l03l04.

EXAMPLE 2 The mixture of 58 mg of 7-[3a-(3B-hydroxy-ltransoctenyl)-4B-hydroxy-tetrahydro-2B-thienyl heptanoic acid, 3 ml of dioxane, 1 mlof water, 4 ml of methanol and 52 mg of sodium periodate is stirred at 0for 24 hours and evaporated at room temperature. The residue is taken upin saturated aqueous sodium chloride, the mixture extracted four timeswith ethyl 13 acetate-diethyl ether l l the extract dried andevaporated. The residue is subjected to preparative thinlayerchromatography on silica gel and eluted with the less polar phaseobtained from ethyl acetate-acetic acidmethanol-hexane-water(110:30z35zl00), to yield the corresponding and B-sulfoxides of theformula Of U) having Rf 0.41 or m.p. llO-l25 and Rf= 0.50 or m.p. l l0ll8 respectively.

In the analogous manner the 7-[ la and [3-oxo-3a- (3a-hydroxyl-trans-octenyl )-4a-hydroxy-tetrahydro- ZB-thienyll-heptanoic acids areobtained, having Rf= 0.38 or m.p. l05l and Rf=0.49 or m.p. 96l03respectively.

EXAMPLE 3 To the solution of 45 mg of 7-[ l,l-dioxo-[3a-(3-oxoltrans-octenyl)-4B-( Z-tetrahydropyranyloxytetrahydro-ZB-thienyll-heptanoic acid methyl ester in 3 ml ofdioxane-methanol l :l 50 mg of sodium borohydride are added and themixture stirred for half hour at room temperature. It is diluted with 20ml of diethyl ether, washed with water and saturated aqueous sodiumchloride, dried and evaporated. The residue is dissolved in 2 ml ofmethanol and 50 ul of 2N sulfuric acid while stirring and the mixture isallowed to stand at room temperature overnight. It is diluted with 20 mlof diethyl ether, washed with water and saturated aqueous sodiumchloride, dried and evaporated. The residue is subjected to preparativethin-layer chromatography on silica gel and eluted twice with ethylacetatemethylene chloride (3:2), to yield the 7-[ l ,l-dioxo-3a-(3B-hydroxyl -trans-octenyl)-4B-hydroxy-tetrahydro-2fl-thienyll-heptanoic acid methyl ester of the formula ca o -coocahaving Rf 0.18 or m.p. 88-90.

The mixture of 48 mg thereof, 1 ml of methanol and 0.2 ml of 2N aqueoussodium hydroxide is allowed to stand at room temperature overnight andevaporated. The residue is taken up in 1 ml of water and 2 ml ofsaturated aqueous sodium chloride, the mixture acidified with 2Nsulfuric acid and extracted with diethyl ether. The extract is washedwith water and saturated aqueous sodium chloride, dried and evaporated,to yield the corresponding free acid melting at 87-89.

The starting material is prepared as follows: The mixture of 14 g of7-cyanoheptanal, 38 g of ethyl triphenylphosphoranylidene-acetate andI00 ml of benzene is refluxed for 15 hours and evaporated. The residueis triturated with diethyl ether, filteren :d the filtrate evaporated.The residue is allowed to stand overnight in the refrigerator,triturated with the minimum amount of diethyl ether, the suspensionfiltered, the filtrate evaporated, the residue distilled and thefraction boiling at l30l38/0.l mm Hg collected, to yield the9-cyano-2-nonenoic acid ethyl ester of the formula O COOC H5 (on CN 26which is used as such without further purification.

To the solution of 24 g thereof in 240 ml of ethanol, l.8 g of sodiumborohydride are added during 5 minutes while stirring at 0. After Vahour, the mixture is poured onto ice water, extracted with diethylether, the extract washed with water and saturated aqueous sodiumchloride, dried and evaporated. Each gram of the residue ischromatographed on 30 g of silica gel and the column eluted with ethylacetate-methylene chloride (lzl to yield the2-(6-cyanohexyl)-4-hydroxytetrahydrothiophen-3-carboxylic acid ethylester of the formula COOC H5 having the correct elemental analysis.

The mixture of 900 mg thereof, 538 mg of dihydropyrane, 45 mg of picricacid and [0 ml of methylene chloride is allowed to stand at roomtemperature overnight. lt is evaporated, the residue taken up in diethylether, the solution washed three times with ID percent aqueous potassiumbicarbonate, once with water and saturated aqueous sodium chloride,dried and evaporated, to yield the 2-( o-cyanohexyl )4-( 2-tetrahydropyranyloxy)-tetrahydrothiophen-3- carboxylic acid ethyl esterof the formula 1 coos n,

showing in the IR. spectrum bands at 2931, 2855, 2254 and 1730 cm.

To the solution of 5.0 l g thereof in 200 ml of tetrahydrofuran, 900 mgof lithium aluminum hydride are added while stirring at 20. After 3hours, 200 ml of diethyl ether are added, followed by a few drops ofmethanol and water. It is filtered, the filtrate evaporated, the residuesubjected to preparative thin-layer chromatography on silica gel andeluted twice with ethyl acetate-methylene chloride (1:9), to yield the7- (3a-hydroxymethyl-4B-( Z-tetrahydropyranyloxytetrahydro-2B-thienyll-heptanoic acid nitrile of the formula showing inthe LR. spectrum bands at 3500, 2930, 2855 and none at I730 cm".

The mixture of 1.3 g thereof, ml of methanol, 5 ml of water and 2 ml of20 percent aqueous potassium hydroxide is heated in a sealed tube toll5l20 for 72 hours. It is evaporated, the residue taken up in 10 ml ofwater and 10 ml of saturated aqueous sodium chloride, the solutionneutralized with dry ice and extracted with diethyl ether. The extractis dried, evaporated, the residue taken up in an excess of etherealdiazomethane and the solution evaporated after A: hour, to yield the 7-[3a-hyd roxymethyl-4B-( 2-tetrahydropyranyloxytetrahydro-Zfi-thienyll-heptanoic acid methyl ester of the formula ---ca-o1i (CHE -coocn showing in the IR. spectrum bands at 3455, i720, 1100.1060 and I020 cm.

To the solution of 400 mg thereof in 200 ml of methylene chloride, thesolution of [.6 g of pyridinechromium trioxide complex are added at onceand the mixture stirred at room temperature for minutes. It is washedwith water, dried, treated with charcoal. fil- 'CH -OH t 5 (La coocatered and evaporated. The residue is taken up in 20 ml of diethyl ether,and 1.6 g of l-tri-nbutylphosphoranylidene-Z-heptanone are added whilestirring and the mixture allowed to stand at room temperature overnight.It is evaporated, the residue subjected to preparative thin-layerchromatography on silica gel and eluted with ethyl acetate-methylenechloride (1:9) to yield the desired 7-[l,l-dioxo-3oz-(3-oxol-transoctenyl )-4B-( 2-tetrahydropyranyloxytetrahydro-ZB-thienyl]-heptanoic acid methyl ester showing in the N.M.R.spectrum peaks at 6.92, 6.79, 6.59, 6.32, 4.72 and 3.55 ppm.

EXAMPLE 4 To the solution of 400 mg 7-[3a-(3-oxo-l-trans'octenyl)-4B-(Z-tetrahydropyranyloxy)-tetrahydro-2B- thienyll-heptanoicacid methyl ester in 20 ml of ethanol, mg of sodium borohydride areadded and the mixture stirred for half hour at 0". It is diluted with200 ml of diethyl ether, washed with water and saturated aqueous sodiumchloride, dried and evaporated. The residue is dissolved in 20 ml ofmethanol, 10 mg of p-toluenesulfonic acid are added while strrring andthe mixture is allowed to stand at room temperature overnight. It isdiluted with 200 ml of diethyl ether, washed with water and saturatedaqueous sodium chloride, dried and evaporated. The residue is subjectedto preparative thin-layer chromatography on silica gel and eluted withethyl acetate-methylene chloride (I21), to yield the7-[3a-(3B-hydroxy-l-trans-octenyl)-4B- hydroxytetrahydro-2B-thienyll-heptanoic acid methyl ester of the formula havingan Rf 0.302 and showing in the NMR spectrum bands at 5.5, 3.67, 2.28 and0.90 ppm.

The mixture of 82 mg thereof, l0 ml of methanol and 1 ml of 0.1N aqueoussodium hydroxide is allowed to stand at room temperature overnight andevaporated. The residue is taken up in 10 ml of water and 10 ml ofsaturated aqueous sodium chloride, the mixture acidified with 0. l Nhydrochloric acid and extracted with diethyl ether. The extract iswashed with water and saturated aqueous sodium chloride, dried andevaporated, to yield the corresponding free acid, which is identicalwith the compound obtained according to Example I.

The starting material is prepared as follows: The solution of Li g of7-[3a-hydroxymethyl-4B-( 2-tetrahydropyranyloxy)-tetrahydro-2B-thienyl]- heptanoic acid methylester in 5 ml of dry toluene is added dropwise to the mixture, preparedby adding 0.6 ml of dimethylsulfide to a solution of 0.8 g of N-chlorosuecimmide in 25 ml of toluene at 0, while stirring at 25. Aftertwo hours 0.84 ml of triethylamine are added, cooling is discontinuedand after five minutes 20 ml of diethyl ether are added. The mixture iswashed with water, 0.lN hydrochloric acid and saturated aqueous sodiumchloride, dried and evaporated, to yield the 7-[3a-formyl-4fl-(2-tetrahydropyranyloxy)-tetrahydr02B-thienyllheptanoic acid methyl ester,having an Rf= 0.64 on silica gel plates eluted with ethylacetate-methylene chloride l:4).

The mixture of L1 g thereof, [.1 g of Hri-n-butylphosphoranylidene-2-heptanone and 20 ml of diethyl ether is stirred atroom temperature overnight and evaporated. The residue is subjected topreparative thin-layer chromatography on silica gel plates (l mm thick),eluted with ethyl acetate-methylene chloride 1:l and the bandcorresponding to Rf= 0.534 yields the 7-[ 3a-( 3-oxol -trans-octenyl)-4/3-( 2- tetrahydropyranyloxy)-tetrahydro-2B-thienyl]- heptanoic acidmethyl ester.

EXAMPLE 5 To the solution of 200 mg of7-[l,1-dioxo-3a-(3-oxol-trans-octenyl)-4B-(2-tetrahydropyranyloxy)-tetrahydro-ZB-thienyl]-heptanoic acid methyl ester in 25 ml oftetrahydrofurane, cooled to 78, 6 ml of lmolar methylmagnesium iodidesolution in diethyl ether are added dropwise while stirring. After onehour the mixture is diluted with wet diethyl ether, washed with water,dried and evaporated. The residue is dissolved in 8 ml of methanol, 40mg of p-toluenesulfonic acid are added and the mixture is kept at 5Covernight. It is neutralized with triethylamine, evaporated and theresidue taken up in diethyl ether. The solution is washed with water,dried, evaporated and the residue crystallized from diethyl ether, toyield the 7-[l,ldioxo-3a-(3B-hydroxy-3a-methyl-l-trans-octenyl1-4B-hydroxy-tetrahydro-2B-thienyll-heptanoic acid methyl ester melting at74.77".

The mixture of 36 mg thereof, 0.5 ml of methanol and 50 pl of 20 percentaqueous potassium hydroxide is stirred at room temperature overnight andevaporated. The residue is dissolved in 4 ml of water and l ml ofsaturated aqueous sodium chloride, then neutralized by adding dry-iceand extracted six times with diethyl ether. The combined extracts arewashed with water, dried and evaporated to yield the 7-[ l,l-dioxo- 3a-(3B-hydroxy-3a-methyll -trans-octenyl )-4B-hydroxy-tetrahydro-ZB-thienyll-heptanoic acid of the formula ll omelting at l22l23.

EXAMPLE 6 To the solution of 400 mg of 7-[ l ,l -dioxo-3a-(3-oxol-trans- -phenylpentenyl )-4B-( 2-tetrahydropyranyloxy)-tetrahydro-2B-thienyl)- heptanoic acid methylester in 30 ml of ethanol, 87 mg of sodium borohydride are added and themixture stirred for half hour at room temperature. It is diluted with200 ml of diethyl ether, washed with water and saturated aqueous sodiumchloride, dried and evaporated. The residue is dissolved in 20 ml ofmethanol, mg of p-toluenesulfonic acid are added while stirring and themixture is allowed to stand at room temperature overnight. It is dilutedwith 200 ml of diethyl ether, washed with water and saturated aqueoussodium chloride, dried and evaporated. The residue is subjected topreparative thin-layer chromatography on silica gel and eluted twicewith ethyl acetate-methylene chloride (4: l to yield the 7-[l,l-dioxo-3a-(3B-hydroxy-ltrans-S-phenylpentenyl)-4B-hydroxy-tetrahydro-2B-thienyll-heptanoic acid methyl ester of the formula having Rf 0.29 orm.p. 6365.

The mixture of 148 mg thereof, 9 ml of methanol and L2 ml of 2N aqueoussodium hydroxide is allowed to stand at room temperature overnight andevaporated. The residue is taken up in 10 ml of water and 20 ml ofsaturated aqueous sodium chloride, the mixture acidified with 2Nsulfuric acid and extracted with diethyl ether. The extract is washedwith water and saturated aqueous sodium chloride, dried and evaporated,to yield the corresponding free acid melting at l22l24.

The starting material is prepared as follows: To the solution of 500 mgof 7-[ l ,1-dioxo-3a-hydroxymethyl- 4B-( Z-tetrahydropyranyloxy)-tetrahydro-2B-thienyl heptanoic acid methyl ester in 200 ml ofmethylene chloride, the solution of 2.0l g of pyridinechromium trioxidecomplex are added at once and the mixture stirred at room temperaturefor 15 minutes. It is washed with water, dried, treated with charcoal,filtered and evaporated. The residue is taken up in 20 ml of diethylether, and 725 mg of l-tri-nbutylphosphoranylidene-S-phenyl-2-pentanoneare added while stirring and the mixture allowed to stand at roomtemperature overnight. it is evaporated, the residue subjected topreparative thin-layer chromatography on silica gel and eluted withethyl acetatemethylene chloride (35:65), to yield the 7-[l,l-dioxo- 3a-(3-oxol -trans-5-phenylpentenyl )-4B-( 2-tetrahydropyranyloxy)-tetrahydro-2B-thienyl]- heptanoic acid methylester showing in the NMR spec trum peaks at 7.22, 6.36, 6.l, 5.67, L58and 1.38 ppm.

EXAMPLE 7 The solution of l00 mg of 7-[l,ldioxo-3a-(3B- hydroxyl-trans-octenyl )-4B-hydroxy-tetrahydro-2B- thienyl1-heptanoic acid in 5ml of diethyl ether is treated with excess of ethereal diazomethane at 0for hour and the solution evaporated under reduced pressure, to yieldthe corresponding methyl ester melting at 88 to 90 afterrecrystallization from ethyl acetate-methylene chloride (3:2).

in a similar manner the methyl esters of the acids illustrated by theprevious examples are prepared.

EXAMPLE 8 50 mg of 7-[l,l-dioxo-3a-(3B-hydroxy-l-transoctenyl1-4B-hydroxy-tetrahydro-ZB-thienyl]-heptanoicacid are hydrogenated overnight in 10 ml of ethanol over 10 mg oftris-(triphenylphosphine)-rhodium (l) chloride at room temperature andatmospheric pressure. The catalyst is filtered off, the filtrateevaporated, the residue taken up in diethyl ether and the solutiondecolorized with charcoal, to yield the 7-[l,l-dioxo- Bar-lBB-hydroxyoctyl )-4B-hydroxy-tetrahydro-ZB- thienyH-heptanoic acid ofthe formula Analogously the unsaturated compounds of the re mainingexamples can be hydrogenated to the corresponding saturated compounds.

EXAMPLE 9 Analogous to the methods illustrated in the previous examplesthe following compounds of the formula H\ a .C=C H OH A ethyl acetate Bdiethyl ether C diethyl ether D ethyl acetate methylene chloride ll:lmethylene chloride methanol-hexane methylene chloride (4:!

EXAMPLE 10 Preparation of injection ampuls each containing 50 mg of theactive ingredient:

hcptanoic acid l70 g l.l.l-Trichloro-2-methyl-2-propanol 85 gPolysorbate 80 B5 Methylcellulose I cps 1.785 g Sodiumcarboxymethylcellulose 70 MV g Sodium chloride III; Igt

Water for in jection PROCEDURE The chloropropanol is first dissolved in13 It of water at 90, then the sodium carboxymethylcellulose is addedwhile stirring, followed by the methylcellulose and stirring iscontinued for IS minutes. The mixture is allowed to stand at 10 for 12hours, combined with the polysorbate and the solution of the sodiumchloride and active ingredient in 250 ml of water each. The resultingsolution is made up to l7 It with water, filtered through a sinteredglass funnel, the filtrate placed into 2 It sterilized bottles,steam-sterilized at l00 for 3.25 hours and filled into 5 ml ampuls withstandard equipment.

This injectable solution l0 g/ml) can be used in the preparation of aninfusion solution. by adding the proper amount thereof to infusionsaline, to obtain a solution containing l0 ug of the active ingredientper ml (10g/ml).

In the analogous manner injectionor infusionsolutions are prepared withthe remaining compounds of the invention, especially those illustratedby the previous examples.

I claim:

1. A pharmaceutical composition comprising a compound, corresponding tothe formula wherein each of R and R is lower alkyl, lower alkenyl, loweralkynyl, (3 to 7 ring-membered cycloalkyl or cycloalkenyl)-C,,,H whereinm is an integer from 0 to 4, or Ph-C,,H,,,, wherein Ph is phenyl, (loweralkyl)- phenyl, (lower alkoxy)-phenyl, (lower alkylenedioxy)- phenyl,(halogeno)-phenyl. (trifluoromethyl)-phenyl, (nitro)-phenyl or (di-loweralkylamino)-phenyl, n is an integer from I to 4 and x such from O to 2,or R is also hydrogen, Ph, an alkali metal or one equivalent of analkaline earth metal and R, is also (lower alkoxy or halo)-lower alkyl,A is ethylene or ethenylene, R, and R are hydrogen or lower alkyl, orthe 1,2- dihydroderivatives thereof containing no double-bond at thelchain-carbon atom, in an amount sufficient to produce aprostaglandin-like effect together with a pharmaceutical excipient.

2. A composition as claimed in claim I, wherein the effective compoundcorresponds to the formula heptanoic acid.

an integer

1. A PHARMACEUTICALLY COMPOSITION COMPRISING A COMPOUND, CORRESPONDINGTO THE FORMULA
 2. A composition as claimed in claim 1, wherein theeffective compound corresponds to the formula
 3. A composition asclaimed in claim 1, wherein the effective compound is 7-(1,1-dioxo-3Alpha -(3 Beta -hydroxy-1-trans-octenyl)-4 Beta -hydroxy-tetrahydro-2Beta -thienyl)-heptanoic acid.